Background Expanded DNA repeats are associated with many hereditary neurological disorders, among the most common of which is Huntington’s disease (HD), a severe neuropsychiatric disorder caused by a CAG repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations could affect depression risk in the general population. Therefore, we aimed to assess the contribution of the whole spectrum of HTT CAG repeat length variations to depression susceptibility.
Methods We determined HTT CAG repeat size in all participants from two well-characterised Dutch cohorts – the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Old People – in whom DNA samples were available (including 2165 depressed and 1058 non-depressed persons). The association between HTT CAG repeat size and depression risk was assessed through binary logistic regression as well as non-parametrically by calculating odds ratios (OR) for each repeat with respect to the modal size.
Results In both cohorts separately as well as combined there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in the longer allele in which both relatively short and relatively large alleles were associated with an increased risk of depression as compared to alleles near the middle of the distribution (β = −0.292 and β = 0.006 for the linear and the quadratic term, respectively; both p ≤ 0.009 after adjustment for the effects of sex, age and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (OR = 0.66, 95% CI: 0.48 to 0.91).
Conclusion We found a non-linear association between HTT CAG repeat size and risk of lifetime depression in which lifetime depression risk increased with both relatively short and relatively large alleles. Our study provides proof-of-principle that repeat polymorphisms could act as hitherto unappreciated but important complex genetic modifiers of depression.
- CAG repeat polymorphism